Differential responses of cerebral and renal oxygenation to altered perfusion conditions during experimental cardiopulmonary bypass in sheep.

We tested whether the brain and kidney respond differently to cardiopulmonary bypass (CPB) and to changes in perfusion conditions during CPB. Therefore, in ovine CPB, we assessed regional cerebral oxygen saturation (rSO2 ) by near-infrared spectroscopy and renal cortical and medullary tissue oxygen tension (PO2 ), and, in some protocols, brain tissue PO2 , by phosphorescence lifetime oximetry. During CPB, rSO2 correlated with mixed venous SO2 (r = 0.78) and brain tissue PO2 (r = 0.49) when arterial PO2 was varied. During the first 30 min of CPB, brain tissue PO2 , rSO2 and renal cortical tissue PO2 did not fall, but renal medullary tissue PO2 did. Nevertheless, compared with stable anaesthesia, during stable CPB, rSO2 (66.8 decreasing to 61.3%) and both renal cortical (90.8 decreasing to 43.5 mm Hg) and medullary (44.3 decreasing to 19.2 mm Hg) tissue PO2 were lower. Both rSO2 and renal PO2 increased when pump flow was increased from 60 to 100 mL kg-1 min-1 at a target arterial pressure of 70 mm Hg. They also both increased when pump flow and arterial pressure were increased simultaneously. Neither was significantly altered by partially pulsatile flow. The vasopressor, metaraminol, dose-dependently decreased rSO2 , but increased renal cortical and medullary PO2 . Increasing blood haemoglobin concentration increased rSO2 , but not renal PO2 . We conclude that both the brain and kidney are susceptible to hypoxia during CPB, which can be alleviated by increasing pump flow, even without increasing arterial pressure. However, increasing blood haemoglobin concentration increases brain, but not kidney oxygenation, whereas vasopressor support with metaraminol increases kidney, but not brain oxygenation.

Dose equivalence for metaraminol and noradrenaline - A retrospective analysis.

BACKGROUND: Noradrenaline and metaraminol are commonly used vasopressors in critically ill patients. However, little is known of their dose equivalence. METHODS: We conducted a single centre retrospective cohort study of all ICU patients who transitioned from metaraminol to noradrenaline infusions between August 26, 2016 and December 31, 2020. Patients receiving additional vasoactive drug infusion were excluded. Dose equivalence was calculated based on the last hour metaraminol dose (in µg/min) and the first hour noradrenaline dose (in µg/min) with the closest matched mean arterial pressure (MAP). Sensitivity analyses were performed on patients with acute kidney injury (AKI), sepsis and mechanical ventilation. RESULTS: We studied 195 patients. The median conversion ratio of metaraminol to noradrenaline was 12.5:1 (IQR 7.5-20.0) for the overall cohort. However, the coefficient of variation was 77% and standard deviation was 11.8. Conversion ratios were unaffected by sepsis or mechanical ventilation but increased (14:1) with AKI. One in five patients had a MAP decrease of >10 mmHg during the transition period from metaraminol to noradrenaline. Post-transition noradrenaline dose (p < 0.001) and AKI (p = 0.045) were independently associated with metaraminol dose. The proportion of variation in noradrenaline dose predicted from metaraminol dose was low (R2 = 0.545). CONCLUSIONS: The median dose equivalence for metaraminol and noradrenaline in this study was 12.5:1. However, there was significant variance in dose equivalence, only half the proportion of variation in noradrenaline infusion dose was predicted by metaraminol dose, and conversion-associated hypotension was common.

International pharmacy survey of peripheral vasopressor infusions in critical care (INFUSE).

PURPOSE: The primary objective was to determine the proportion of hospitals that administered norepinephrine peripheral vasopressor infusions (PVIs) in critically ill adult patients. Secondary objectives were to describe how norepinephrine is used such as the maximum duration, infusion rate and concentration, and to determine the most common first-line PVI used by country. MATERIALS AND METHODS: An international multi-centre cross-sectional survey study was conducted in adult intensive care units in Australia, US, UK, Canada, and Saudi Arabia. RESULTS: Critical care pharmacists from 132 institutions responded to the survey. Norepinephrine PVIs were utilised in 86% of institutions (n = 113/132). The median maximum duration of norepinephrine PVIs was 24 h (IQR 24-24) (n = 57/113). The most common maximum norepinephrine PVI rate was between 11 and 20 µg/min (n = 16/113). The most common maximum norepinephrine PVI concentration was 16 µg/mL (n = 60/113). Half of the institutions had a preference to administer another PVI over norepinephrine as a first-line agent (n = 66/132). The most common alternative PVI used by country was: US (phenylephrine 41%, n = 37/90), Canada (dopamine 31%, n = 5/16), UK (metaraminol 82%, n = 9/11), and Australia (metaraminol 89%, n = 8/9). CONCLUSIONS: There is variability in clinical practice regarding PVI administration in critically ill adult patients dependent on drug availability and local institutional recommendations.

Comparison of metaraminol versus no metaraminol on time to resolution of shock in critically ill patients.

OBJECTIVE: There is limited evidence to support metaraminol use in critically ill patients. Metaraminol is not included as a vasopressor choice in international guidelines for the management of shock. Nevertheless, metaraminol is used in rates up to 42% in this patient population. The objective of this study was to investigate the effectiveness of metaraminol for the treatment of critically ill patients with shock. METHODS: A single-centre retrospective matched observational study was conducted in a 54-bed intensive care unit of a tertiary hospital. Patients aged 16 years or older who were admitted from 2017 to 2019 with shock were included. Patients treated with metaraminol and norepinephrine (MET-NOR) were compared with those treated with norepinephrine without metaraminol (NOR). The primary outcome was the time to resolution of shock defined as the time to cessation of vasopressors. The secondary outcome was vasopressor-free days until 28 days. RESULTS: There were 286 patients included in this study, including 143 patients in each group. The median time to resolution of shock was 44 hours (IQR 28-66 hours) in the MET-NOR group compared with 27 hours (IQR 14-63 hours) in the NOR group (95% CI of median difference 7 to 19 hours; p<0.01). The Cox regression analysis for the time to resolution of shock showed no significant difference between groups (HR 1.24, 95% CI 0.96 to 1.60; p=0.10). However, the proportional hazards assumption was not met (p<0.01). The median number of vasopressor-free days until 28 days was 26 days (IQR 24-27 days) in the MET-NOR group compared with 27 days (IQR 25-27 days) in the NOR group (95% CI of median difference -0.8 to -0.1 day; p<0.01). CONCLUSION: In critically ill patients, metaraminol may be associated with a longer time to resolution of shock compared with those who do not receive metaraminol.

Cardiovascular Drug Administration Errors During Neuraxial Anesthesia or Analgesia-A Narrative Review.

The prevalence and harm associated with inadvertent neuraxial cardiovascular (CV) medication administration errors are unknown. This review aims to analyze neuraxial CV drug administration errors and associated clinical consequences. The secondary objective is to identify the causes and contributory factors in order to prevent future incidents. The author reviewed reports of accidental administration of CV medications via neuraxial routes during spinal or epidural anesthesia or analgesia published in the last 5 decades (1972-2022). Twenty-seven publications reported neuraxial administration of 10 different CV drugs among patients aged 1 to 81. Seventeen of the 33 errors occurred via the epidural route. Digoxin (9 patients), ephedrine (6), metaraminol (4), labetalol (4), and dopamine (3) were frequently involved in the incidents. Intrathecal digoxin (8 patients) was associated with paraplegia and encephalopathy, of whom 4 pregnant women scheduled for elective cesarean delivery sustained permanent lower limb neurologic deficits. Reversible systemic hemodynamic changes were predominant following the administration of epidural inotropes (dobutamine, dopamine, and epinephrine) and vasopressors (ephedrine and metaraminol). Most administrations (30 out of 32) were only bolus injections. All were preventable skill-based errors. The human factor analysis classification system (HFACS) identified poor organizational climate, inadequate supervision of junior doctors, deficiencies in neuraxial task processes, and incorrect visual perception of objects. The HFACS suggests CV medication safety strategies should include better education and training of junior doctors, modifications in neuraxial anesthesia practices, and careful handling of the CV drug ampoules and syringes.

Effect of Weight-Adjusted Phenylephrine, Norepinephrine, and Metaraminol for Elective Cesarean Delivery on Neonatal Acid-Base Status: A Randomized Controlled Trial.

Purpose: Many previous trials have compared the effects of different vasoactive drugs on cesarean section patients, but their infusion rate is based on experience rather than high-quality evidence. It is difficult to judge whether the effect of vasoactive drug comes from the better choice or a more appropriate at rates of vasoactive drugs. The effect of vasoactive drugs at the rates of the 90% effective dose needs to be verified and compared. Patients and Methods: Women undergoing elective caesarean delivery under combined spinal-epidural anaesthesia were randomized to receive phenylephrine or norepinephrine or metaraminol infusion at the rate that was assumed to be the 90% effective dose. Anesthetic management was standardized and included fluid loading with 10 mL/kg of Ringer. The primary outcome was the umbilical artery pH. Results: 78 patients were included. The umbilical artery pH was not significantly different among the three groups (phenylephrine group: 7.33 ± 0.03 vs norepinephrine group: 7.33 ± 0.04 vs metaraminol group: 7.33 ± 0.04, P = 0.99). There were no significant differences in the incidence of hypotension, hypertension, bradycardia, and nausea and vomiting among the three groups. The SBP of the phenylephrine group was significantly higher than that of the metaraminol group (adjustive P value = 0.005). Conclusion: Phenylephrine (0.54 µg/kg/min) or metaraminol (2 µg/kg/min) or norepinephrine (0.08 µg/kg/min) administered to healthy patients with elective cesarean section after spinal anesthesia has no significant effect on the acid-base balance of the fetus.

Kinetic and mechanism study of the spontaneous, solvent- and base-catalyzed degradation of the precursor of the ß-nitro alcohol metaraminol by combining HPLC/electronic circular dichroism/theoretical methods.

Chiral ß-nitro alcohols are key intermediates in the synthesis of a wide range of active pharmaceutical ingredients. Despite their massive use for pharmaceutical applications, in-depth kinetics studies concerning their stability during formation and transformation reactions are scarce in the literature. In this study, the (1R,2S)-1-(m-benzyloxy)-2-nitro-1-propanol) (BNA), the precursor of the metaraminol, was selected as a molecular model and the retro-Henry reaction was explored by a multidisciplinary approach involving HPLC, electronic circular dichroism and theoretical methods. The enantio-, diastereo-, and chemo-selective high-performance liquid chromatographic method for determining the purity of ß-nitro alcohol during its formation and degradation is based on the use of an amylose-derived chiral stationary phase under normal-phase eluent conditions. The influence of various factors (e.g. temperature, type of reaction solvent, basic and acid catalysts) on the degradation kinetics has been investigated. The retro-Henry reaction was found to be the major degradation of BNA, under spontaneous, solvent- and base-catalyzed conditions, resulting in the formation of its precursors 3-benzyloxybenzaldehyde and nitroethane.

Comparison of Metaraminol, Phenylephrine, and Norepinephrine Infusion for Prevention of Hypotension During Combined Spinal-Epidural Anaesthesia for Elective Caesarean Section: A Three-Arm, Randomized, Double-Blind, Non-Inferiority Trial.

BACKGROUND: A direct comparison of phenylephrine, metaraminol, and norepinephrine in preventing hypotension during spinal anaesthesia for elective caesarean section has never been made. PATIENTS AND METHODS: Seventy-five parturients scheduled for elective caesarean section were randomly assigned into the three groups. After spinal anaesthesia induction, patients received a bonus dose of vasopressor (norepinephrine 4ug, phenylephrine 50ug, or metaraminol 250ug) combined with continuous infusion (norepinephrine 8ug/mL, phenylephrine 100ug/mL, or metaraminol 500ug/mL) at a rate of 30 mL/h to prevent hypotension. The primary outcome was umbilical arterial (UA) pH and other intraoperative data were also recorded. RESULTS: The UA pH was 7.32±0.03 for metaraminol, 7.31±0.03 for phenylephrine, and 7.31±0.03 for norepinephrine. The 95% CI of MD was -0.011 to 0.026 comparing metaraminol with norepinephrine and 0.0181 to 0.0182 comparing phenylephrine with norepinephrine. Both lower bounds of the 95% CI of MD were above the predetermined lower boundary of clinical non-inferiority of -0.03, indicating both metaraminol and phenylephrine were non-inferior to norepinephrine. Moreover, the incidence of hypotension was lower in metaraminol compared with norepinephrine (P = 0.01). However, the incidence of hypertension was significantly lower in both phenylephrine and metaraminol compared with norepinephrine. CONCLUSION: Both metaraminol and phenylephrine were non-inferior to norepinephrine with respect to neonatal UA pH when used as a bolus and continuous infusion to prevent hypotension during combined spinal-epidural anaesthesia for elective caesarean section.

Repurposing old drugs as novel inhibitors of human MIF from structural and functional analysis.

Human macrophage migration inhibitory factor (MIF) is an important pro-inflammatory cytokine that plays multiple pleiotropic functions. It is considered as a promising therapeutic target for the infectious, autoimmune, and cardiovascular diseases and cancers. The development of MIF inhibitors has not been translated into clinical success despite decades of research. Given the time and cost of developing new drugs, existing drugs with clarified safety and pharmacokinetics are explored for their potential as novel MIF inhibitors. This study identified five known drugs that could inhibit MIF's tautomerase activity and MIF-mediated cell chemotaxis in RAW264.7 cells. It was found that compounds D2 (histamine), D5 (metaraminol), and D8 (nebivolol) exhibited micromolar-range inhibition potency close to the positive control ISO-1. Kinetics and the mechanism for inhibition were subsequently determined. Moreover, the detailed inhibitor-binding patterns were investigated by X-ray crystallography, computational molecular docking, and structure-based analysis. Therefore, this study elucidates the molecular mechanism of repurposed drugs acting on MIF and provides a structural foundation for lead optimization to promote the clinical development of MIF-targeted drugs.

Dose equivalence between metaraminol and norepinephrine in critical care.

AIMS: The aim of this study was to determine the conversion dose ratio between continuous infusion metaraminol and norepinephrine in critically ill patients with shock. METHODS: A retrospective cohort study was conducted in adult patients with shock admitted to an intensive care unit from 29 October 2018 to 30 October 2019 and who transitioned from metaraminol monotherapy to norepinephrine monotherapy. Mean arterial pressure (MAP) and infusion doses for both drugs were collected at hourly intervals; 2 hours before to 5 hours after switching from metaraminol monotherapy to norepinephrine monotherapy. The conversion dose ratio was defined as the ratio of metaraminol (µg.kg-1 .min-1) : norepinephrine (µg.kg-1 .min-1 ) required to achieve a similar MAP. RESULTS: A total of 43 out of 144 eligible patients were included. The median age was 68 years (IQR 56-76) and 22 (51%) were male. There was no significant difference between the baseline MAP during metaraminol monotherapy (median 71 mm Hg, IQR 66-76) and the post-transition MAP during norepinephrine monotherapy (median 70 mm Hg, IQR 66-73) (P = .09). The median conversion dose ratio between metaraminol and norepinephrine was 13 (IQR 7-24). In the sensitivity analyses, the median conversion dose ratio using the maximum and the mean norepinephrine infusion dose was 8 (IQR 5-16) and 12 (IQR 8-23), respectively. CONCLUSION: A conversion dose ratio of 10:1 (metaraminol µg.kg-1 .min-1 :norepinephrine µg.kg-1 .min-1 ) may be used in critically ill patients with shock to account for ease of calculations and variability of the conversion ratio in the primary and sensitivity analyses.

Pharmacoepidemiology of metaraminol in critically ill patients with shock in a tertiary care hospital.

BACKGROUND: Metaraminol is increasingly used as a vasopressor in critically ill patients. Nevertheless, there remains limited evidence to support its use in international guidelines for management of shock. OBJECTIVES: The aim of the study was to describe the pharmacoepidemiology of metaraminol in critically ill patients with shock. METHODS: A retrospective observational study was conducted in an intensive care unit (ICU) in Sydney, Australia. Patients admitted during a 1-year time frame who received metaraminol intravenous infusions for management of shock were included. RESULTS: A total of 152 patients were included. When metaraminol was used, it was the most common first-line vasopressor started for management of shock (97%, n = 147) and was used as monotherapy in 53% (n = 81) of patients. The median duration of metaraminol infusion in the ICU was 7 h (interquartile range [IQR] = 3 to 19), and the median maximum metaraminol infusion rate in the ICU was 4.0 mg/h (IQR = 2.5 to 6.0). Peripheral vasopressor infusions were used in 96% (n = 146/152) of patients for a median duration of 7 h (IQR = 2 to 18). In all these cases, the peripheral vasopressor used was metaraminol (100%, n = 146/146). Patients were commonly switched from metaraminol to noradrenaline infusions after insertion of a central venous catheter (R2 = 0.89). Patients treated with metaraminol monotherapy had a lower Acute Physiology and Chronic Health Evaluation III score (58 vs 68; median difference = -9, 95% confidence interval = -16 to -3; p < 0.01) and a shorter duration of overall vasopressor use in the ICU (12 vs 39 h, median difference = -24 h, 95% confidence interval = -31 to -18; p < 0.01) than those treated with combination vasopressors. No extravasation injury was reported in the study cohort. CONCLUSIONS: Metaraminol is often administered as a first-line peripheral vasopressor in the ICU and is used as a single agent in patients with lower severity of shock.

Strategies that improve renal medullary oxygenation during experimental cardiopulmonary bypass may mitigate postoperative acute kidney injury.

Renal medullary hypoxia may contribute to cardiac surgery-associated acute kidney injury (AKI). However, the effects of cardiopulmonary bypass (CPB) on medullary oxygenation are poorly understood. Here we tested whether CPB causes medullary hypoxia and whether medullary oxygenation during CPB can be improved by increasing pump flow or mean arterial pressure (MAP). Twelve sheep were instrumented to measure whole kidney, medullary, and cortical blood flow and oxygenation. Five days later, under isoflurane anesthesia, CPB was initiated at a pump flow of 80 mL kg-1min-1 and target MAP of 70 mm Hg. Pump flow was then set at 60 and 100 mL kg-1min-1, while MAP was maintained at approximately 70 mm Hg. MAP was then increased by vasopressor (metaraminol, 0.2-0.6 mg/min) infusion at a pump flow of 80 mL kg-1min-1. CPB at 80 mL kg-1min-1 reduced renal blood flow (RBF), -61% less than the conscious state, perfusion in the cortex (-44%) and medulla (-40%), and medullary Po2 from 43 to 27 mm Hg. Decreasing pump flow from 80 to 60 mL kg-1min-1 further decreased RBF (-16%) and medullary Po2 from 25 to 14 mm Hg. Increasing pump flow from 80 to 100 mL kg-1min-1 increased RBF (17%) and medullary Po2 from 20 to 29 mm Hg. Metaraminol (0.2 mg/min) increased MAP from 63 to 90 mm Hg, RBF (47%), and medullary Po2 from 19 to 39 mm Hg. Thus, the renal medulla is susceptible to hypoxia during CPB, but medullary oxygenation can be improved by increasing pump flow or increasing target MAP by infusion of metaraminol.

Metaraminol use during spinal anaesthesia for caesarean section: a meta-analysis of randomised controlled trials.

INTRODUCTION: During caesarean section, the use of a vasopressor is often required to achieve haemodynamic stability of the parturient. Metaraminol is a vasopressor used in this context in some countries. However, the differences between metaraminol and other vasopressors remain unclear. METHODS: A search of the PubMed, Cochrane Library, and Embase databases was performed to identify randomised controlled trials comparing the use of metaraminol with other vasopressors during spinal anaesthesia at caesarean section. The selected studies were subjected to meta-analysis and risk-of-bias assessment. RESULTS: Four randomised, controlled trials met the selection criteria and 409 parturients who underwent an elective caesarean section were included in this meta-analysis. The quality of these trials was good. Metaraminol was associated with higher umbilical arterial pH (standardised mean difference [SMD] 0.82, 95% CI 0.01 to 1.62, P=0.05); a lower incidence of fetal acidosis (RR 0.08, 95% CI 0.01 to 0.63, P=0.02); and a lower incidence of nausea or vomiting (RR 0.16, 95% CI 0.04 to 0.57, P=0.0005) than was ephedrine. Metaraminol resulted in higher umbilical arterial pH (SMD 0.42, 95% CI 0.15 to 0.68, P=0.002) but a higher incidence of reactive hypertension (RR 1.80, 95% CI 1.32 to 2.46, P=0.0002) than did phenylephrine. CONCLUSION: The results of this study showed that for spinal anaesthesia at elective caesarean section, metaraminol may be a more suitable vasopressor than ephedrine and its effects are at least not inferior to those of phenylephrine.

Predrawn prehospital medications are microbiologically safe for up to 48 hours.

BACKGROUND: Prehospital medical teams are commonly required to administer a range of medications for urgent stabilisation and treatment. The safe preparation of medications during resuscitation requires attention, time and resources, and can be a source of medication error. In our two road and HEMS (Helicopter Emergency Medical Service) prehospital services, medication errors are mitigated by predrawing commonly used medications to set concentrations daily (Hunter Retrieval Service, HRS) or second-daily (CareFlight Sydney, CFS). However, there are no published data confirming that such practice is microbiologically safe. METHODS: A convenience sample of 299 predrawn medication syringes with syringe dwell times up to 48 hours were collected at the end of their operational deployment. Predrawn medication syringes collected for culture were ketamine, midazolam, fentanyl, thiopentone, rocuronium, suxamethonium, metaraminol and normal saline. The samples were incubated and cultured at a tertiary hospital pathology laboratory using best-practice methodology for non-tissue samples. The samples were collected from June 2017 to February 2018. RESULTS: The mean dwell times ranged from 30.7 hours (fentanyl at HRS) to 48.5 hours (rocuronium at CFS). None of the 299 cultured samples yielded significant micro-organisms. One sample of suxamethonium with a syringe dwell time of 34 hours grew Bacillus cereus but was likely a contaminant introduced during sample collection. CONCLUSION: Predrawing of the eight studied medications for urgent prehospital procedures appears to be a microbiologically safe practice with syringe dwell times up to 48 hours.

The Impact of Ageing on 11C-Hydroxyephedrine Uptake in the Rat Heart.

We aimed to explore the impact of ageing on 11C-hydroxyephedrine (11C-HED) uptake in the healthy rat heart in a longitudinal setting. To investigate a potential cold mass effect, the influence of specific activity on cardiac 11C-HED uptake was evaluated: 11C-HED was synthesized by N-methylation of (-)-metaraminol as the free base (radiochemical purity >95%) and a wide range of specific activities (0.2-141.9 GBq/µmol) were prepared. 11C-HED (48.7 ± 9.7MBq, ranged 0.2-60.4 µg/kg cold mass) was injected in healthy Wistar Rats. Dynamic 23-frame PET images were obtained over 30 min. Time activity curves were generated for the blood input function and myocardial tissue. Cardiac 11C-HED retention index (%/min) was calculated as myocardial tissue activity at 20-30 min divided by the integral of the blood activity curves. Additionally, the impact of ageing on myocardial 11C-HED uptake was investigated longitudinally by PET studies at different ages of healthy Wistar Rats. A dose-dependent reduction of cardiac 11C-HED uptake was observed: The estimated retention index as a marker of norepinephrine function decreased at a lower specific activity (higher amount of cold mass). This observed high affinity of 11C-HED to the neural norepinephrine transporter triggered a subsequent study: In a longitudinal setting, the 11C-HED retention index decreased with increasing age. An age-related decline of cardiac sympathetic innervation could be demonstrated. The herein observed cold mass effect might increase in succeeding scans and therefore, 11C-HED microPET studies should be planned with extreme caution if one single radiosynthesis is scheduled for multiple animals.

Sympathetic denervation in patients with ischemic cardiomyopathy and risk on ventricular tachy-arrhythmias. A pilot study.

BACKGROUND: Patients with ischemic cardiomyopathy (ICM) are at risk for ventricular arrhythmias and are protected by an implantable cardioverter defibrillator (ICD). Visualization of cardiac sympathetic innervation may play an additional role to left ventricular ejection fraction (LVEF) in identifying those patients who will benefit from ICD therapy. The purpose of this study was to detect the role of sympathetic denervation in the genesis of ventricular arrhythmias in ICM patients. METHODS: Twenty patients with ICM and LVEF <30% were included in this pilot study. Included patients were equally stratified into two groups: no history of arrhythmias (group A) and recurrent arrhythmias (group B). All patients underwent cardiac sympathetic denervation (using carbon-11 labelled meta-hydroxy-ephedrine ([11C]-mHED)), myocardial ischemia and viability detection. Patients were followed up to one year after the imaging studies. RESULTS: Mean age was 63±7.5 years. Mean global retention of [11C]-mHED was 0.055±0,012 min-1, and was not different between the two patient groups: 0.056±0.011 min-1 vs. 0.054±0.013 min-1 for group A vs. group B, respectively. During follow-up, seven patients developed ventricular arrhythmias, and four patients died. No difference in [11C]-mHED retention was found between patients with and without ventricular arrhythmia during follow-up. However, size of denervated area was larger in patients who died during follow-up: 10±1 segments vs. 6±2 segments, P=0.002. CONCLUSIONS: Cardiac sympathetic innervation is impaired in patients with ischemic cardiomyopathy. All-cause mortality occurred in those patients with large areas of [11C]-mHED defect.